The preparation of 1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[ b,d]-pyran-9-ones has been reported by Fahrenholtz, Lurie and Kierstead, J. Am. Chem. Soc., 88, 2079 (1966), 89, 5934 (1967). The reported synthesis of such compounds included the reaction of a 5-substituted resorcinol with diethyl .alpha.-acetylglutarate to provide the corresponding ethyl 4-methyl-5-hydroxy-7-substituted coumarin-3-proprionate. Cyclization of the latter compound by reaction with a metal hydride afforded a 1-hydroxy-3-substituted-6,7,8,10-tetrahydro-6H-dibenzo[b,d]pyran-6,9-dione . The 9-ketone group was next protected by ketal formation, and then treatment of the ketal with methyl magnesium bromide, followed by deketalization, provided a 1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8-tetrahydro-6H-dibenzo[b,d]py ran-9-one. Reduction of the .DELTA..sup.10(10a) double bond afforded predominantly dl-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H -dibenzo[b,d]pyran-9-one, with only minor quantities of the corresponding dl-6a,10a-cis isomer being formed.
While the dl-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-d ibenzo[b,d]pyran-9-ones are pharmacologically active, their activity is less than that of the corresponding trans derivatives. The cis compounds are, however, useful as intermediates leading to pharmacologically active trans isomers. It recently has been discovered, for example, that reaction of a dl-cis-dibenzo[b,d]pyran-9-one derivative with aluminum chloride or aluminum bromide in a solvent such as dichloromethane effects complete isomerization to afford the corresponding dl-trans-derivative. Such dl-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H -dibenzo[b,d]-pyran-9-ones recently have been found to be effective in the treatment of anxiety and depression, as described for example in U.S. Pat. Nos. 3,928,598, 3,944,673, and 3,953,603.
It is an object of this invention to provide a one-step process for preparing substantially exclusively dl-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-d ibenzo[b,d]pyran-9-ones from readily available starting materials. Such compounds can then be converted to the corresponding more active dl-trans isomers.